2021 Fiscal Year Research-status Report
Investigation on the arrhythmogenecity of Nav1.5-TRPM4 channel complex
| Project/Area Number |
20K16126
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| Research Institution | Fukuoka University |
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Principal Investigator |
胡 耀鵬 福岡大学, 医学部, 助教 (40708476)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | Arrhythmogenicity / TRPM4 / Nav1.5 / Numerical simulation / Conduction block |
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| Outline of Annual Research Achievements |
The patch clamp experiments were focused on several TRPM4 mutations associated with cardiac conduction disorders, e.g., E7K and Q854R mutant. The functional interaction between Nav1.5 and TRPM4 channel was characterized by cable simulation. The results are summarized as follows: 1) By the Iono-C/A recording technique, the gain of function TRPM4 mutations more readily open at more negative membrane potentials and at lower [Ca2+]i condition. It is induced by enhancing the voltage and Ca2+ dependencies of the rate constants of opening (α) and decreasing those of closing (β). These mutations accelerate the closed-to-open state (C-O) transition, meanwhile decelerate the reverse (O-C) transition. 2）1D-cable simulation models incorporating TRPM4 channel and its mutant gating were constructed. The preferred opening by the gain of function mutants tends to cause conduction block. In addition, the decreases in dV/dtmax and CV are consistent with the depolarizing shifts of the resting membrane potential (RMP). The level of RMP plays an important role to determine Nav availability. In this context, the extent of the observed RMP shift reasonably accounts for the decrease in Nav availability, especially at AP upstroke which is estimated from its voltage-dependent inactivation curve. Therefore these results reveal that excessive TRPM4 activities at resting conditions would facilitate Nav inactivation during diastole, thereby slowing the subsequent generation and propagation of the AP.
During this year, the results was published in International Journal of Molecular Sciences.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Patch clamp experiments and numerical simulation models strongly suggest that our technique approaches could be instrumental for predicting the electrophysiological changes in the hearts of conduction failures.
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| Strategy for Future Research Activity |
We are going to focus on possible animal or tissue model for the assessment of the interaction of TRPM4 and Nav1.5. Electrophysiological investigation along with histological and biochemical data, will be used to examine the temporal relationships among arrhythmias and TRPM4 or Nav1.5 expression/activities. These results will help us to confirm and modify the cardiac model which we have constructed.
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| Causes of Carryover |
Research costs will be spent on animal feeding as well as consumables for cell culture, molecular biological, biochemical and electrophysiological experiments. To present the outcome of our study, we are going to join several conferences and submit our study results to certain academic journals.
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Research Products
(2 results)
